study of carfilzomib and vorinostat for relapsed or refractory lymphoma

Conditions: Lymphoma

Summary: this will be a phase i study of carfilzomib in combination with vorinostat in patients with relapsed/refractory b-cell lymphomas. combination therapy with proteosome inhibitor pr-171 and hdac inhibitors is highly synergistic in primary dlbcl cells, and both classes of drugs can also synergize powerfully to induce cell death in bortezomib-resistant cells. the purpose of this study is to see if vorinostat can combine with carfilzomib and to safely find the recommended phase ii dose.

study drugs: vorinostat, a class i/ii pan-histone deacetylase inhibitor (hdaci), was the first approved agent og this class on the basis of activity in refractory cutaneous t-cell lymphoma. lethal mechanisms include anti-apoptotic protein down-regulation, up-regulation of proapoptotic proteins, induction of ros, death receptor up-regulation, and disruption of chaperone function and dna-repair proteins. carfilzomib, is a irreversible proteasome inhibitor of the epoxyketone class that exhibits a high level of selectivity for the proteosome. this agent induced a dose- and time-dependent inhibition of proliferation, ultimately leading to apoptosis. study drug administration: if you are found to be eligible to take part in this study: * vorinostat po twice daily on days 1, 2, 3, 8, 9, 10, 15, 16 and 17. * daily carfilzomib 30 minutes infusion on days 1, 2, 8, 9, 15, 16. * administer first daily dose of vorinostat prior to carfilzomib on days 1, 2, 8, 9, 15, 16 * cycle repeated every 28 days, up to 13 cycles. carfilzomib will be given at 20mg/m2 for days 1 and 2 of cycle 1 only, then escalated to the higher dose indicated in the schema on day 8 of cycle 1 and thereafter. carfilzomib treatment is to be done early in the morning and have a minimum of a 6 hour observation period after the infusion. for patients with good tolerability to carfilzomib during the first cycle, an observation period of 2 hours is recommended. a minimum of 16 hours should separate doses of carfilzomib, so that the day 1 dose may be given in the afternoon and the day 2 dose in morning during cycle 2 and subsequent cycles for patients who tolerate the drug well. if two out of 6 patients do not tolerate the initial dose of 20 mg/m2 carfilzomib on days 1 \& 2 followed by 27 mg/m2 carfilzomib for subsequent doses and 200 mg/day bid vorinostat, the next patient should be dose reduced to 20 mg/m2 carfilzomib and 100 mg/day bid vorinostat. study visits: * baseline within 4 weeks of cycle 1 day 1. * ct or physical exam. * bone marrow if needed to follow disease status. * pet recommended but not required. to document complete response (cr), a pet is required. * optional research tumor biopsy. * peripheral blood obtained for pd prior to initiation of treatment and at 48 hours +/- 6 hours after receiving first dose of carfilzomib , and at off study. * end of treatment restaging will take place 6-8 weeks after completion of treatment and will include an assessment by the physician, labs, and a tumor response evaluation. * after completion of restaging exams, follow up exams will take place every 6 months for 2 years and then annually until disease progression or initiation of another treatment. * an off study visit will take place at the time of disease progression or initiation of another treatment, which will include assessment by the physician,a tumor response evaluation, labs, and a final pd sample, by the patient's consent.

Eligibility criteria:
inclusion criteria: * histologically confirmed b-cell lymphomas, excluding cll (chronic lymphocytic leukemia), that is recurrent or refractory after at least one prior therapy and for which no other potentially curative therapy is available. * age ≥ 18 years * ecog performance status (ps) ≤ 2 * laboratory parameters * if sll, lymphocyte count \< 5,000/µl * absolute neutrophil count ≥ 1000/µl * platelets ≥ 75,000/µl * creatinine ≤ 1.5x upper limit of normal or calculated creatinine clearance \> 40ml/min * ast, alt ≤ 2.5 x upper limit of normal (uln) * bilirubin ≤ 2.0 mg/ml * serum potassium ≥ 3.5 meq/l and serum magnesium ≥ 1.7 meq/dl (electrolytes may be corrected with supplementation). * pt \< 1.5 x uln and ptt \< 1.2 x uln (unless receiving therapeutic anticoagulation). * patient is, in investigator's opinion, willing and able to comply with the protocol requirements and offers written informed consent. * female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control ( i.e., oral injectable hormonal methods; barrier methods such as intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence)for the duration of the study. * male subject agrees to use an acceptable method for contraception for the duration of study. exclusion criteria: * history of brain metastasis including leptomeningeal metastasis. * chemotherapy of radiotherapy within 3 weeks prior to entering the study. * prior histone deacetylase inhibitor as cancer treatment. * concurrent treatment with other investigational agents or cancer treatment. * unable to take oral medications. * active ischemic heart disease or congestive heart failure. if there is suspicion of cardiac disease, left ventricular ejection fraction (lvef) must be ≥ 45%, otherwise study to evaluate ef is not required. * persistent blood pressure (bp) of ≥ 160/95 (three separate readings on different days). * history of allergic reactions attributed to compounds of similar chemical or biological composition to carfilzomib and vorinostat. * known clinical significant infection including infection with human immunodeficiency virus (hiv), or active hepatitis b or c, requiring treatment. * serious medical or psychiatric illness likely to interfere with patient participation. * pregnant or nursing. confirmation that a woman is not pregnant must be established by a negative serum pregnancy test result obtained at screening. * pregnancy testing is not required for post-menopausal or surgically sterilized women. * no prior allogeneic stem cell transplant. * patients scheduled for any type of stem cell transplant within 4 weeks of treatment. * patients who have valproic acid for epilepsy can enroll, provided that they stopped drug at least 30 days prior to enrollment and they will be on a stable, effective dose of an alternative anti-seizure medication.